Evolutionary processes have led to neural systems coordinately regulating food intake and physical activity, and simultaneous perturbations of these behaviors are observed in mood and eating disorders. Dysregulation of serotonin systems has been implicated in these disorders, suggesting that a better understanding of serotonergic regulation of ingestion and activity has important implications for elucidating their pathophysiology. The serotonin 2c receptor (5HT2CR) plays an important role in serotonergic regulation of ingestion and activity, and some aspects of 5HT2CR regulation appear to be mediated by the melanocortin system. The focus of the proposed work is to identify and understand the function of the neural circuits through which serotonin regulates ingestion and activity by delineating the extent to which 5HT2CR and melanocortin pathways interact in regulating these behaviors. Aim 1. The effects of simultaneous disruption of 5HT2CR and MC4R will be used to identify behaviors regulated by 5HT2CR that depend on activation of the melanocortin system. Aim 2. Neural circuits involved in the coordinated regulation of ingestion and activity whose function is disrupted by these mutations will be identified by correlating induction of Fos-like immunoreactivity with food-deprivation induced hyperactivity. Aim 3. The functional roles of 5HT2CR in the arcuate and ventral medial hypothalamus are hypothesized to be distinct. This hypothesis will be tested by specifically inactivating 5HT2CR in each of these regions and by assessing the impact of inactivation on patterns of ingestion and activity. Aim 4. A better understanding of the functional role of 5HT2CR-expressing neurons in each of these regions will be obtained by identifying their specific neural connections using selective expression of a transgenic transneuronal tracer. This K08 Award will provide the candidate with training in quantitative behavioral analysis, mouse genomic manipulation, and neuroanatomic techniques, thereby allowing the candidate to develop a multi-disciplinary approach to the study of behaviors relevant to psychiatry using the mouse as a model system. In addition, the training will foster the candidate's development as an independent investigator in academic psychiatry.